Cell hyper-proliferation has long been considered as an important etiological factor of cardiovascular diseases and cancer. Vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty play a central role in cardiovascular diseases, the current leading cause of death in the western countries and the predicted number one killer worldwide by 2020, but the underlying molecular mechanism is poorly understood. Using RNA differential display analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and age- and gender-matched Wistar Kyoto rats (WKY), we have identified a novel gene, named hyperplasia suppressor gene (HSG) which encodes a protein of 757 amino acids and is widely expressed in various rat tissues. We have also cloned human and mouse HSG genes, which share 95.2 and 98.4 % sequence homology, respectively, with rat HSG (rHSG). The expression of rHSG is markedly downregulated in hyperplasic SHR VSMCs relative to normal WKY VSMCs. In addition, rHSG expression is also overtly down-regulated by proliferation-stimulating factors such as platelet-derived growth factor (PDGF)?Cbasic fibroblast growth factor (bFGF), and endothelin-1 (ET-1) in cultured primary WKY VSMCs. Enforced expression of rHSG using adenoviral gene transfer markedly inhibits growth factors-mediated VSMC proliferation by inhibition of ERK1/2 MAPK activation and subsequent cell cycle arrest in G1/Go, and reduces balloon injury-induced neointimal formation by 90% in vivo, thereby preventing balloon injury-associated restenosis. In addition, HSG alos markedly inhibits proliferation and induces apoptosis in many cancer cell lines. Thus, we have identified and characterized a widely expressed and highly conserved novel gene, HSG, which exhibits an important role in regulating cell proliferation and cell death in VSMCs as well as amny other cell types. These findings not only reveal a fundamental biological function of the ubiquitously expressed and phylogenetically well-conserved gene, but also define a novel genetic pathway for cell proliferative diseases.